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EZH2 in lymphoid lineage specification and commitment

EZH2 淋巴谱系规范和承诺

基本信息

批准号：
8622415
负责人：
BARBARA L. KEE
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8622415
关键词：
Acute Lymphocytic Leukemia Address Antibodies Antigens B-Lymphocytes Binding Biological Bone Marrow Cells Cell Differentiation process Cells Chromatin Chronic Lymphocytic Leukemia Clinical Common Lymphoid Progenitor Complex Cytotoxic T-Lymphocytes Data Development Diffuse Disease EZH2 gene Frequencies Gene Expression Gene Targeting General Transcription Factors Genes Germ Lines Global Change Goals Histones Immune Immune response Immune system In Vitro Invaded Investigation Lead Lymphocyte Lymphoid Lymphoid Cell Lysine Malignant lymphoid neoplasm Measures Mediating Modeling Molecular Multiprotein Complexes Mus Mutation Pathway interactions Polycomb Population Proteins Recruitment Activity Repression Research Specific qualifier value T-Lymphocyte Testing Therapeutic arm base cytokine gene repression genome-wide histone methyltransferase in vitro Assay in vivo inhibitor/antagonist insight leukemia/lymphoma loss of function mRNA Expression pathogen progenitor programs public health relevance receptor response transcription factor

项目摘要

EZH2 is the histone methyltransferase component of the polycomb repressor complex 2 (PRC2), which is required for repression of numerous lineage specifying transcription factors during development. Recent studies have revealed that both gain and loss of function of EZH2 can contribute to lymphoid malignancy. Here we will test the hypothesis that EZH2 is required for commitment of common lymphoid progenitors to the adaptive lymphocyte (B and T cell) fates but not to innate lymphocyte (ILC1 and ILC2) fates. We will test this hypothesis by examining the consequences of Ezh2 inactivation in common lymphoid progenitors under competitive and non-competitive conditions by flow cytometric analysis of lymphoid cells and through the use of in vitro assays that measure both frequency of differentiation and commitment to a given lineage. In parallel we will identify EZH2 target genes by examining the global changes in gene expression in lymphocytes and their progenitors caused by EZH2-deficiency as well as identifying genes that are bound by EZH2 and fail to undergo H3K27 trimethylation, the hallmark of EZH2 activity, in EZH2-deficient cells. Taken together, our study will provide significant insight into the mechanisms controlling gene expression during lymphocyte lineage specification and commitment. In addition, we will gain a better understanding of how EZH2 mutations lead to leukemia and lymphoma and how treatment of these diseases with EZH2 inhibitors might influence normal lymphocyte development.

EZH2是多梳阻遏物复合物2的组蛋白甲基转移酶组分（PRC2），其是抑制许多谱系特异性转录所需的发展过程中的因素。最近的研究表明，无论是增益和损失的 EZH 2的功能可能导致淋巴恶性肿瘤。在这里，我们将测试假设EZH2是共同的淋巴祖细胞的承诺，适应性淋巴细胞（B和T细胞）的命运，但不是先天性淋巴细胞（ILC1和ILC2）命运我们将通过检查Ezh2失活的后果来检验这一假设。在竞争性和非竞争性条件下通过流动的共同淋巴祖细胞淋巴细胞的细胞计数分析，并通过使用体外测定，分化的频率和对给定谱系的承诺。同时，我们将通过检查EZH2靶基因表达的总体变化， EZH2缺陷引起的淋巴细胞及其祖细胞，被EZH2结合并且不能经历H3K27三甲基化的基因， EZH2活性，在EZH2缺陷细胞中。总的来说，我们的研究将提供重要的深入了解淋巴细胞谱系过程中控制基因表达的机制规范和承诺。此外，我们将更好地了解如何 EZH2突变导致白血病和淋巴瘤以及如何治疗这些疾病 EZH2抑制剂可能会影响正常的淋巴细胞发育。